Peptide-Based Drug Design

15
Synthesis of a Multivalent, Multiepitope Vaccine
Construct
Laszlo Otvos, Jr.
Summary
A major challenge to contemporary peptide chemistry is to reproduce highly complex
active sites or complexes of native proteins. In addition to the need for the combination
of different peptide fragments, true protein mimics designed for therapeutic use
frequently require the incorporation of multiple copies of given active domains in a
biologically relevant spatial arrangement. Perhaps the best examples for this line of
drug design are subunit vaccine candidates against extracellular domains of ion-channel
proteins. One of our earlier constructs containing four copies of the ectodomain of
the M2 protein of influenza virus together with two independent T-helper cell epitopes
induced protective antibody production in mice. Here I describe an improved synthesis
of the M2-based multiepitope and multivalent peptide construct. In general, the synthetic
strategy outlined here can serve as a model for the orthogonal N-terminal and side-chain–
protecting scheme during the preparation of large, complex peptides or small, engineered
proteins.
Key Words: Automated peptide synthesis; influenza virus; oligolysine scaffold;
orthogonal side-chain protection; protective antibody; T-helper cell determinant.
1. Introduction
Peptide fragments represent the biologically active domains of native
proteins. However, many recognition processes require the presence of multiple
independent protein fragments, co-activators, or chaperones (1). In addition,
it was long considered that peptides without carrier modules are unable to
enter cells (2), although since the turn of the millennium this assumption has
been increasingly challenged (3). Thus, to elicit the desired and full biological
From: Methods in Molecular Biology, vol. 494: Peptide-Based Drug Design
Edited by: L. Otvos, DOI: 10.1007/978-1-59745-419-3 15, © Humana Press, New York, NY
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